Transplant Arteriosclerosis: Viral and Host Mechanism

描述（由申请人提供）：本计划的基本目标 在慢性移植物排斥的免疫发病机制是解决“TA：病毒和 宿主机制”通过理解这种常见的 心脏移植受者的慢性排斥反应表现。程序 项目重点关注人类巨细胞病毒（HCMV）在 与免疫病理和炎症调节相结合， 进展为TA的患者。这项研究涉及一个大的，有组织的多层次的 160例心脏移植受者的评估。外周血和 将在第一次肌内膜活检中收集八次样本， 每年和连续三年进行免疫、病毒学和 与TA相关的炎症指标。第一个项目在 该计划将重点关注HCMV特异性CD 4和CD 8 T细胞的贡献， 细胞记忆/效应器功能在从潜伏或 原发感染的开始和TA的进展。该项目将 还研究了细胞的活化状态。逆相关是 进展为TA的风险与功能性 HCMV特异性T细胞。该计划的第二个项目将侧重于 HCMV DNA和病毒基因表达的诱导在患者中的风险 TA.灵敏的溶液和原位DNA扩增和杂交 在后续研究中，将使用方法跟踪病毒DNA和mRNA水平 期本项目将研究病毒编码或诱导的 趋化因子（UL 146/vCXC-1）和趋化因子受体（US 28）在 TA的进展病毒株的促炎能力和 高度可变的UL 146趋化因子基因，从患者进展到TA将是 研究了预计病毒学指标在 升级到TA。第三个项目将确定硝酸的影响， 氧化合酶（NOS）途径，重点是两个主要的变化，可以 在患者中测量：（i）血管超氧阴离子（O2-）增加，和 (ii)ADMA的增加。本项目将研究HCMV感染 通过细胞因子诱导的氧化损伤的改变来增强这些异常。 应激和ADMA积累。人巨细胞病毒对血管内皮细胞和血管内皮细胞的影响 炎症性NOS通路在TA进展期间是预期的。重要的是， 所有三个项目将在外周血中并行工作 细胞/血浆/血清以及直接在肌内膜活检中 采样时间如此密集的纵向研究应该提供最好的 可能的设置，以揭示协会和确定HCMV的贡献 到TA。其机制、预后价值及治疗要点 针对HCMV的干预，对HCMV的免疫应答，免疫激活 免疫病理事件和NOS通路的作用都可能 这是这些合作努力的结果。

DESCRIPTION (provided by applicant): The fundamental objective of this Program in Immunopathogenesis of Chronic Graft Rejection is to address "TA: Viral and Host Mechanisms" by understanding pathogenic processes underlying this common manifestation of chronic rejection in heart transplant recipients. The Program Project focuses on the contribution of human cytomegalovirus (HCMV) in conjunction with immunopathogenic and inflammatory modulation that develops in patients who progress to TA. The study involves a large, organized multi-level evaluation of 160 heart transplant recipients. Peripheral blood and endomyocardial biopsy specimens will be collected eight times over the first year and three times in successive years to follow immune, virologic and inflammatory indicators that will be correlated with TA. The first project in this program will focus on the contribution of the HCMV-specific CD4 and CD8 T cell memory/effector function during the reactivation from latent or the initiation of primary infection and the progression to TA. This project will also investigate the activation state of cells. An inverse correlation is expected between the risk of progression to TA and the frequency of functional HCMV-specific T cells. The second project of this program will focus on levels of HCMV DNA and the induction of viral gene expression in patients at risk of TA. Sensitive solution and in situ DNA amplification and hybridization approaches will be used to follow viral DNA and mRNA levels in the follow-up period. This project will investigate the role of virus encoded or -induced chemokine (UL146/vCXC-l) and chemokine receptor (US28) expression in progression of TA. The proinflammatory capacity of viral strains and the highly variable UL146 chemokine gene, from patients progressing to TA will be investigated. An increase in virological indicators is expected during progression to TA. The third project will determine the impact of the Nitric Oxide Synthase(NOS) pathway by focusing on two major changes that can be measured in patients: (i) increases in vascular superoxide anion (O2-), and (ii) increases in ADMA. This project will investigate how HCMV infection augments these abnormalities via cytokine induced alterations in oxidative stress and ADMA accumulation. An impact of HCMV on endothelial and inflammatory NOS pathways is expected during progression to TA. Importantly, all three projects will work in parallel in peripheral blood cells/plasma/serum as well as directly in endomyocardial biopsies at all sampling times. Such an intense longitudinal study should provide the best possible setting to uncover associations and identify the contribution of HCMV to TA. The mechanisms, prognostic value and points of therapeutic intervention-directed at HCMV, the immune response to HCMV, immune activation and immunopathogenic events and the role of NOS pathways will all potentially emerge as a result of these collaborative efforts.